The Madonna laboratory continues the work of Dr. Bernard L. Mirkin in the area of regulation of neuroblastoma growth and differentiation, and has made great strides in expanding the knowledge of chemotherapy resistance and identifying potential targets for therapy.
Drug resistance poses a major obstacle in the treatment of human cancers. As the most common extracranial solid tumor of childhood, neuroblastoma accounts for 15 percent of cancer-related deaths in children, with resistance to chemotherapeutic drugs being a major factor. Our long-term goal is to uncover new therapeutic targets and treatment protocols that will lead to preventing or reversing the development of the multidrug resistant phenotype in order to improve the prognosis for children with high-risk, relapsed and recurrent neuroblastoma.
The primary thrust of our research team has focused on studies to identify the basic biological processes that regulate adaptation of malignant tumor cells to stressful environments, such as those produced by anti-cancer drugs, and thereby permit their survival in the presence of agents that would normally kill them. Understanding these processes will help cancer researchers develop novel chemotherapeutic strategies. Our group has directed its attention to tumors that predominate during early childhood, such as neuroblastoma. Understanding the role of differential expression and activation on the various signaling pathways will lead to a better understanding of neuroblastoma growth and metastasis, and will lead to potential new targets for treatment of this very aggressive tumor of young children.
Current Research Projects
Role of Glycolysis in the Development of Drug Resistant Neuroblastoma Tumor Cells
The process of basic glucose metabolism is key to understanding the differences between the wild type drug sensitive cells and drug resistant cells in both normoxic and hypoxic conditions. Biochemical and molecular studies suggest there are alterations in the metabolic tumor cells that are increasingly recognized as a mechanism by which cells survive the stress of chemotherapy. This inherent difference between malignant and non-malignant cells offers an approach to treat cancer that would allow specificity of drug treatment against malignant cells while sparing the non-malignant cells.
Identifying Receptor(s) of Midkine in Conferring Drug Resistance in Neuroblastoma Tumor Cells
Our group has identified midkine as a putative survival molecule responsible for cytoprotective signaling between drug resistant and drug sensitive neuroblastoma and other cancer cells. Identifying the midkine receptor(s) and downstream signaling pathways may identify potential tumor markers or therapeutic targets that, once suppressed, may reverse drug resistance.
Role of Notch Pathway in the Development of Drug Resistant Neuroblastoma Tumor Cells
The Notch signaling pathway plays critical mechanistic roles in cell proliferation, survival, apoptosis and differentiation, which affects the development and function of many organs. Emerging evidence revealed that Notch is involved in anti-cancer drug resistance, indicating that targeting Notch may be a novel therapeutic approach for the treatment of cancer by overcoming drug resistance of cancer cells, which could lead to the elimination of cancer stem cells (CSCs) or epithelial mesenchymal transition (EMT) type cells that are typically drug resistant and are believed to be the root cause of tumor recurrence.
List of publications indexed in PubMed by the Madonna Laboratory
Fei Chu, MD, PhD, Research Assistant Professor
Sandra Clark, BS, CLSCC, Laboratory Manager
Yi-Yong Qiu, MD, Senior Research Associate
Kathryn Solka, PhD, Postdoctoral Associate
Sandra Clark, Laboratory Manager
Image above from: Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo. Chu F, Naiditch JA, Clark S, Qiu YY, Zheng X, Lautz TB, Holub JL, Chou PM, Czurylo M, Madonna MB. ISRN Oncol. 2013 Sep 3;2013:518637. doi: 10.1155/2013/518637.